Cell Type-Specific Proteins that Promote Resilience to Cognitive Aging and Alzheimer's Disease

促进认知衰老和阿尔茨海默病恢复能力的细胞类型特异性蛋白质

基本信息

批准号：
10846926
负责人：
CATHERINE COOK KACZOROWSKI
金额：
$ 155.84万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10846926
关键词：
Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amino Acids Amyloid Attention Autopsy Behavior Cells Chronology Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Cognitive aging Cognitive deficits Communities Complex DNA Data Data Set Databases Disease Disease Progression Electrophysiology (science)Environmental Risk Factor Exhibits Gene Expression Gene Expression Profile Genes Genetic Genetic Engineering Genetic Risk Genetic Transcription Genetic Variation Genomics Grant Hand Hippocampus Human Human Genetics Human Genome Immune Impaired cognition Individual Ion Channel Knowledge Knowledge Portal Label Late Onset Alzheimer Disease Learning Link Mediating Memory Memory impairment Meta-Analysis Metadata Methods Microglia Molecular Molecular Analysis Molecular Target Mouse Strains Mus Mutation Neurobehavioral Manifestations Neurons Pathology Pathway interactions Patients Phenotype Population Predisposition Protein Biosynthesis Proteins Proteome Proteomics RNA Research Resources Sampling Shiga-Like Toxin I Synapses Synaptic plasticity System Technology Testing The Jackson Laboratory Time Transcript Translating Variant Work aging brain asymptomatic Alzheimer&apos s disease behavioral phenotyping brain cell brain tissue candidate identification cell type cognitive function cohort data integration drug discovery familial Alzheimer disease genetic approach high dimensionality high risk human data human model human tissue improved knowledge base mouse model multidimensional data neuroinflammation neuronal excitability neuropathology novel prevent promote resilience protective factors protein expression protein protein interaction resilience resilience factor response segregation spatial memory synaptic function tau Proteins therapeutic target transcriptomics usability

项目摘要

Resilience to brain aging and Alzheimer’s disease (AD) is a phenomenon whereby cognitive functioning is better than predicted based on chronological age, genetic risk and/or advanced neuropathology, likely because of the presence of as yet unidentified protective factors. These factors, once identified, are expected to provide key targets for treatment and prevention of AD. However, significant barriers limit discovery of the genetic mechanisms of resilience using human genetic methods alone, including: difficulties in identifying large numbers of individuals with asymptomatic AD, extracting age and interacting genetic effects from complex human genomes, controlling environmental factors, and obtaining brain tissue from asymptomatic AD cases. Moreover, it is well known that transcript abundance is not sufficient to infer protein abundance, as they differ spatially, temporally, and in response to learning tasks. Yet, our ability to discern how proteomes change across aging and AD progression is limited by the impossibility of longitudinal molecular analyses on human brain tissues, as well as the technology needed to profile cell type-specific proteomes associated with susceptibility versus resilience to AD. To fill these significant technological and knowledge gaps, here we will develop a robust pipeline using the most translationally relevant mouse models of human brain aging and AD (i.e., the AD-BXDs and their non-transgenic Ntg-BXDs controls) to obtain a longitudinal knowledge base of proteomes in specific cell types that we have found to exhibit robust changes in gene expression associated with highly susceptible and highly resilient phenotypes. We will focus on the hippocampus as it is required for spatial memory formation and recall in mice and humans, and hippocampus-dependent memory deficits are common in AD. Indeed, our work and preliminary data suggest that mouse strain differences in the age at onset and progression of cognitive deficits in the AD-BXDs (from extremely susceptible to resilient) result from cell type-specific differences in gene expression in the hippocampus. We will integrate these mouse data with clinical and omics data from NIA-sponsored AMP-AD and Resilience-AD Consortia to identify molecular drivers of cognitive resilience. In Aim 1, we will identify cell type-specific changes in neuron and microglia protein expression associated with resilience to AD using bioorthogonal non-canonical amino acid tagging (BONCAT) in AD-BXDs. In Aim 2, we will translate drivers and molecular networks underlying cognitive resilience to human AD cohorts. In Aim 3, we will leverage the unmatched genetic engineering resources at The Jackson Laboratory to functionally validate ‘in-hand’ resilience candidates by determining their effects on memory, hippocampal neuronal excitability, and synaptic plasticity in CRISPRed AD-BXDs. Using this pipeline, we will thereby discover novel and translationally relevant proteins and complexes for consideration under AMP-AD/TREAT-AD drug discovery pipelines to delay or prevent cognitive symptoms in susceptible AD mice, and ultimately AD patients.

对脑部和阿尔茨海默氏病（AD）的韧性是一种现象，在该现象中，认知功能是entic症的风险和/或晚期神经病理学。但是，仅使用人类遗传学方法限制了从复杂人类基因组，控制环境因素的遗传效应以及从无症状的AD病例中获得Bring Bring Bring组织的相互作用的障碍。在空间，时间和响应学习任务时，我们的蛋白体如何改变衰老和AD进展的能力受UMAN脑组织的不可能限制填补大量技术和知识差距Fhuman脑老化和AD（即，AD-BXD及其非转基因NTG-BXDS对照与高度易感和高度弹性的表型相关的基因表达。初步数据表明，小鼠应变差异应变不足的发作和AD-BXDS中认知缺陷的离子（从极易感到弹性）是由于细胞类型特异性的差异而导致的，我们将与海马中的基因express相关。来自NIA赞助的AMP-AD和ROCEILIENTE-AD的OMICS在AIM 1中识别AIM 1中的分子驱动力。在AIM 3中，认知居民的基础网络和杰克逊实验室在功能上验证了其对记忆的效果的弹性，海马神经元的出现性，海马神经元的出现，并在此处发现了by-bxds。在AMP-AD/Trug药物发现Pislins下的翻译甲基蛋白质和复合物，以延迟或预防易感AD小鼠的E症状，并最终导致AD患者。